CIITA (class II transactivator) is the master transcriptional activator regulator of both classical and nonclassical (DM and DOa) MHC-II genes. Mutations within this gene form the genetic basis for the immunodeficiency, type II group A Bare Lymphocyte Syndrome (BLS). CIITA functions by interacting with transcription factors that directly bind the MHC-II promoter such as RFX/CREB and NF-Y. CIITA is an early step of promoter loading, and is required for subsequent epigenetic changes including the recruitment of histone acetylases and methylases to MHC-II promoters. In addition to MHC-II, we recently identified Plexin A1 (Plxnal) as a novel gene that is also regulated by CIITA. This was accomplished by profiling cDNA isolated from primary dendritic cells (DC) obtained from CIITA-deficient mice versus wildtype mice. Plexins comprise a large gene family and are considered the receptor for semaphorin family members. They were initially identified in neurons as important for neuronal guidance and axonal growth and serve as either retractive or attractive signals to guide axonal extension. We use short-hairpin RNA (shRNA) to block Plxnal in DCs and show that Plxnal is important for antigen-specific T cell stimulation. Plxnal shRNA blocks the ability of DCs to stimulate T cells by >80%. Plxnal is not involved in peptide processing or antigenic-peptide binding. Preliminary data suggest it functions in Rho but not cdc42 or Rac activation, and is important in actin polarization. Additional data suggest that Semaphorin 6D (SemaGD) is a candidate T cell ligand for Plxnal on DC. We elect to study three major aspects of the Plxnal and Sema6D pair in primary DC and T cells: (1) The transcriptional regulation of Plxnal by CIITA, by other transcription factors and by histone modifying enzymes; (2) the functional effects of Plxnal on the Rho GTPase pathway; and (3) the interaction of Sema6D on T cells and PIxnAI on DC, and the T cell signaling pathway that is activated upon SemaGD engagement.